Every year, more than 1 million children are exposed to sexual or physical abuse or neglect in the United States.1 Childhood physical or sexual abuse is associated with adult health problems, including somatic symptoms and medical symptoms, such as heart disease, psychological problems, and substance abuse; for many variables, this association is as strong as for patients who are currently experiencing abuse.2 Women with a history of sexual abuse report depression onset earlier in life and appear to engage in more harmful and self-defeating coping strategies.3 Furthermore, a powerful graded relationship exists between adverse childhood experiences and risk of attempted suicide across the life span.4 Individuals who experience early life stress (ELS) are at increased risk for pathophysiological changes in the CNS that increase their vulnerability to stress later in life, which predisposes them to mental and physical disorders.

Numerous biological theories have been proposed to explain the potent and robust effects of ELS on mental and physical health outcomes. One such theory, the diathesis-stress model, posits that:

The chain of events commonly referred to as the “fight-or-flight response” originally evolved to allow an organism to respond when its physical well-being was threatened. This “stress response” is mediated, in part, by the hypothalamic-pituitary-adrenal (HPA) axis that coordinates portions of the nervous and endocrine systems to direct available resources toward the task of overcoming or avoiding the threatening stimulus (stressor).

In the short term, the stress response is extremely adaptive because it shifts biological resources toward physiological functions that promote escape and survival. However, if the stress response becomes chronic because of repeated exposure to stressors, deficits at various levels of the negative feedback system, or both, the result is a sustained increase in the level of stress hormones and the initiation of pathological changes across multiple physiological systems. The consequence is increased vulnerability to stress-related diseases.5

Long-term consequences of ELS exposure

A preponderance of clinical data illustrates the long-term adverse effects of physical and sexual abuse on mental health. Women with a history of sexual abuse are more likely to manifest depressive-like behaviors after stressful life events than are women without such a history.6 In addition, the developmental timing of abuse may contribute to the clinical outcome of exposure to childhood trauma. For example, posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are equally likely to develop in girls abused before age 13. However, PTSD is more likely to develop in those who were abused after age 13.7 This divergence in clinical course may, in part, be linked to the development of the HPA axis and stress coping mechanisms.

In addition to the neuroendocrine and neurotransmitter alterations, there is evidence that ELS may alter brain structure. The hippocampus is a prominent substrate for glucocorticoid-mediated negative feedback on HPA axis activity. Changes in hippocampal cytoarchitecture after chronic stress have been associated with changes in both mood and cognition.8 ELS has been linked to decreased hippocampal volume and may be an important contributor to reduced hippocampal volume in depression.9-11 The concatenation of findings demonstrates that ELS alters the HPA axis and markedly increases the risk of depression and other disorders.

Preclinical studies provide insight into the mechanisms of stress-induced changes in behavior and have demonstrated that ELS exerts both acute and long-term effects on neuroendocrine, cognitive, and behavioral systems.12 Laboratory animals exposed to stressful conditions during development manifest adverse short- and long-term cognitive dysfunction and abnormal behavior associated with alterations of the normal physiology and genetic regulation of the HPA axis.13 Pathological stress responsiveness in adult mammals appears to be mediated in part through the effects of developmental stress on the neural systems that mediate the expression of fear.14 Moreover, the quality of maternal care early in development may be a moderating influence that exerts substantial effects on the ontogeny of the stress response in adult animals.15 Collectively, the data derived from rodent and nonhuman primate studies demonstrate that the effects of ELS continue into adulthood in the form of abnormal behavior and hyperresponsiveness of the HPA axis to environmental stressors.

CHECKPOINTS

►The stress response shifts biological resources toward physiological functions that promote escape and survival; however, if the stress response becomes chronic because of repeated exposure to stressors, deficits at various levels of the negative feedback system, or both, the result is a sustained increase in the level of stress hormones and the initiation of pathological changes across multiple physiological systems. The consequence is increased vulnerability to stress-related diseases.

►Posttraumatic stress disorder (PTSD) and major depressive disorder are equally likely to develop in girls who are abused before age 13; however, PTSD is more likely to develop in those who were abused after age 13.

►Trauma exposure and neglect during both early life and adulthood substantially elevate adult risk for mood and anxiety disorders and alter hypothalamic-pituitary-adrenal (HPA) axis physiology. Exposure to a depressed mother either in utero or in the first months of life may also alter the HPA axis.

Genetic influences

Regardless of the developmental stage during which it occurs, exposure to violence and trauma alone does not produce adverse effects in all exposed women. Thus, the risk of PTSD and/or depression is, in part, heritable.16-18 A major research goal of psychiatric genetics is to understand how genetic variation, both independently and in concert with the environment, influences individual vulnerability to disease.

With respect to stress-related psychiatric illnesses, such as depression and PTSD, a great deal of work has focused on the identification of candidate genes whose allelic variants are thought to contribute to risk of disease in the presence of ELS, such as the serotonin transporter gene, and allelic variants within genes that code for elements of the HPA axis.16,19,20 For those individuals exposed to ELS, both gene 3 gene and gene 3 environment interactions likely influence the development of depression and other disorders. Notably, the genetic variants described by several studies only confer risk of depression and PTSD in the setting of childhood maltreatment. These data highlight the critical role of developmental timing and environmental influences on the expression of genetic risk of psychiatric illness.

Pleiotropic effects of ELS

The research described thus far demonstrates that trauma exposure and neglect during both early life and adulthood substantially elevate adult risk for mood and anxiety disorders and alter HPA axis physiology.21,22 However, the ramifications of ELS reach beyond mental health and behavior and have remarkable implications for a variety of common medical disorders. For example, ELS exposure increases the incidence of systemic inflammation and a variety of medical illnesses, including obesity, cardiovascular disease, cerebrovascular disease, diabetes mellitus, cancer, and autoim-mune disorders.23-27

Furthermore, a graded relationship appears to exist between exposure to trauma and psychiatric/physical health morbidity in adulthood.28 Although the biology of the interrelationships among ELS, mental illness, and physical illness is just beginning to be explored, the lifelong effects of ELS on both mental and physical health are well documented and the HPA axis is a likely mediator of both types of pathophysiology.

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Section Editor: Military Mental Health

Charles C. Engel, MD, MPH, is Senior Health Scientist at the RAND Corporation, a nonprofit, nonpartisan company in Washington, DC. His last military assignment before retiring as an Army Colonel was Associate Chair for Research, Uniformed Services University of the Health Sciences, department of psychiatry, in Bethesda, Maryland. He is the Military Mental Heatlh Section Editor for Psychiatric Times.